The dardarin G 2019 S mutation is a common cause of Parkinson's disease but not other neurodegenerative diseases.

Mutations in the leucine-rich kinase 2 gene (LRRK 2) encoding dardarin, on chromosome 12, are a common cause of familial and sporadic Parkinson's disease. The most common mutation, a heterozygous 6055 G>A transition (G 2019 S) accounts for approximately 3--10% of familial Parkinson's disease and 1--8% sporadic Parkinson's disease in several European-derived populations. Some families with disease caused by LRRK 2 mutations have been reported to include patients with highly variable clinical and pathological features.

Evidence suggesting that Homo neanderthalensis contributed the H2 MAPT haplotype to Homo sapiens.

The tau (MAPT) locus exists as two distinct clades, H1 and H2. The H1 clade has a normal linkage disequilibrium structure and is the only haplotype found in all populations except those derived from Caucasians. The H2 haplotype is the minor haplotype in Caucasian populations and is not found in other populations.

In vivo imaging detects a transient increase in brain arachidonic acid metabolism: a potential marker of neuroinflammation.

In a rat model of neuroinflammation produced by an intracerebral ventricular infusion of bacterial lipopolysaccaride (LPS), we measured the coefficients of incorporation (k*) of arachidonic acid (AA, 20 : 4n-6) from plasma into each of 80 brain regions, using quantitative autoradiography and intravenously injected [1-(14)C]AA. Compared with control rats infused with artificial cerebrospinal fluid (aCSF), k* was increased significantly in 25 brain areas, many of them close to the CSF compartments, following 6-days of LPS infusion. The increases, ranging from 31 to 76%, occurred in frontal, motor, somatosensory, and olfactory cortex, thalamus, hypothalamus, and septal nuclei, and basal ganglia.

Kinetic assessment of general gene expression changes during human naive CD4+ T cell activation.

The consequence of naive CD4+ T cell activation is the differentiation and generation of effector cells. How the engagement of T cell receptors and co-stimulatory receptors leads to profound differential changes is not fully understood. To assess the transcription changes during T cell activation, we developed human T cell specific cDNA microarray gene filters and examined the gene expression profiles in human naive CD4+ T cells for 10 continuous time points during the first 24 h after anti-CD3 plus anti-CD28 (anti-CD3/CD28) stimulation.

Lipid phosphatases in the regulation of T cell activation: living up to their PTEN-tial.

The initiating events associated with T activation in response to stimulation of the T cell antigen receptor (TCR) and costimulatory receptors, such as CD28, are intimately associated with the enzymatically catalyzed addition of phosphate not only to key tyrosine, threonine and serine residues in proteins but also to the D3 position of the myo-inositol ring of phosphatidylinositol (PtdIns). This latter event is catalyzed by the lipid kinase phosphoinositide 3-kinase (PI3K). The consequent production of PtdIns(3,4)P2 and PtdIns(3,4,5)P3 serves both to recruit signaling proteins to the plasma membrane and to induce activating conformational changes in proteins that contain specialized domains for the binding of these phospholipids.

Minimum number of 2'-O-(2-aminoethyl) residues required for gene knockout activity by triple helix forming oligonucleotides.

Triple helix forming oligonucleotides (TFOs) that bind chromosomal targets in living cells may become tools for genome manipulation, including gene knockout, conversion, or recombination. However, triplex formation by DNA third strands, particularly those in the pyrimidine motif, requires nonphysiological pH and Mg(2+) concentration, and this limits their development as gene-targeting reagents. Recent advances in oligonucleotide chemistry promise to solve these problems.

Stop that! Inhibition, sensitization, and their neurovisceral concomitants.

There is increasing evidence that the behavior of living systems can be conceptualized as a self-organizing dynamical system. Moreover, evidence suggests that inhibitory processes give these systems the flexibility that is necessary for efficient functioning in the face of changing environmental demands. The process of sensitization can be conceived as a breakdown of inhibitory neural processes that can lead to maladaptive, perseverative behavior.

BBID: the biological biochemical image database.

The Biological Biochemical Image Database is a WWW accessible relational database of archived images from research articles that describe regulatory pathways of higher eukaryotes. Pathway information is annotated and can be queried in the study of complex gene expression. In this way, complex regulatory pathways can be tested empirically in an efficient manner in the context of large-scale gene-expression systems.

Aged mice exhibit greater mortality concomitant to increased brain and plasma TNF-alpha levels following intracerebroventricular injection of lipopolysaccharide.

Background: Age-related defects in the development of peripheral inflammatory responses have been observed in rodents and humans.

Objective: We examined the effects of age on a centrally injected endotoxin-induced cytokine production and cellular activation in mice.

Methods: Male C57BL/6J (B6) mice, C3H/HeN mice, and C3H/HeJ mice received an intracerebroventricular injection of lipopolysaccharide (LPS) and were sacrificed at various times (2, 4, 8 h) thereafter.

Verbal and figural recognition memory: task development and age associations.

The goal of the present study was to develop and validate parallel tests of verbal and figural delayed-recognition memory with similar task demands and difficulty levels. Such tasks would allow examination of age differences and longitudinal age changes in visual recognition memory for two types of stimuli, activate divergent neural systems, and allow us to use the same procedures within the confines of functional neuroimaging as those we use in standard neuropsychological administration. The tasks introduced here include a delay between target presentation and test phase, are matched in difficulty, and yield moderate levels of performance.

Effects of EGb 761 on fatty acid reincorporation during reperfusion following ischemia in the brain of the awake gerbil.

Transient cerebral ischemia (5 min) releases unesterified fatty acids from membrane phospholipids, increasing brain concentrations of fatty acids for up to 1 h following reperfusion. To understand the reported anti-ischemic effect of Ginkgo biloba extract (EGb 761), we monitored its effect on brain fatty acid reincorporation in a gerbil-stroke model. Both common carotid arteries in awake gerbils were occluded for 5 min, followed by 5 min of reperfusion.

Energy requirements for two aspects of phospholipid metabolism in mammalian brain.

Previous estimates have placed the energy requirements of total phospholipid metabolism in mammalian brain at 2% or less of total ATP consumption. This low estimate was consistent with the very long half-lives (up to days) reported for fatty acids esterified within phospholipids. However, using an approach featuring analysis of brain acyl-CoA, which takes into account dilution of the precursor acyl-CoA pool by recycling of fatty acids, we reported that half-lives of fatty acids in phospholipids are some 100 times shorter (min-h) than previously thought.

DNA repair and transcription in human premature aging disorders.

The human progeroid disorders Cockayne syndrome and Werner syndrome present with several clinical features that are associated with normal aging. These include distinct changes in the skin. The genes responsible for these conditions have recently been cloned and characterized.

Restoration of preferential and strand specific gene repair in group 2 Chinese hamster ovary mutants (UV5) by the XPD (ERCC2) gene.

It has recently been reported that the XPD (ERCC2) gene is an integral component of the basal transcription factor TFIIH. We have studied the direct role of this repair gene on the fine structure of DNA repair in hamster cells. The gene and strand specific DNA repair of UV induced pyrimidine dimers was determined in wild-type hamster cells, in hamster cells harboring a mutation in the gene homologous to the XPD gene and in mutant cells transfected with the human XPD gene.

Incorporation of [U-14C]palmitate into rat brain: effect of an inhibitor of beta-oxidation.

We examined the effect of a clinically therapeutic dose of methyl 2-tetradecylglycidate (McN-3716, methyl palmoxirate, MEP) (2.5 mg/kg), an inhibitor of beta-oxidation of fatty acids, on incorporation of radiolabeled palmitic acid ([U-14C]PAM) from plasma into brain lipids of awake rats. Four hour pretreatment with 2.

Mammalian DNA repair responses and genomic instability.

A cell responds to damage to its DNA in one of three ways: by tolerating the damage, by repairing the damage or by undergoing apoptosis. The latter two responses represent defenses against genomic instability and tumorigenesis resulting from unrepaired damage. There are multiple DNA repair pathways to cope with a variety of damage reflecting the importance of DNA repair in maintaining both cell viability and genomic stability.

Incorporation of [1-carbon-11]palmitate in monkey brain using PET.

Unlabelled: We determined regional incorporation coefficients (k*) of plasma [1-11C]palmitate into stable brain lipids of anesthetized monkeys with PET.

Methods: Carbon-11-palmitate was injected intravenously in untreated animals and in animals pretreated with methyl palmoxirate (MEP), an inhibitor of beta-oxidation of palmitate in the brain and periphery. Plasma radioactivity was followed, and brain radioactivity was determined at various times using PET.

DNA damage, mutation and fine structure DNA repair in aging.

The primary focus of this review is on correlations found between DNA damage, repair, and aging. New techniques for the measurement of DNA damage and repair at the level of individual genes, in individual DNA strands and in individual nucleotides will allow us to gain information regarding the nature of these correlations. Fine structure studies of DNA damage and repair in specific regions, including active genes, telomeres, and mitochondria have begun.

Behavioral assessment of aging in male Fischer 344 and brown Norway rat strains and their F1 hybrid.

Male Fischer-344 (F344) and Brown Norway (BN) rats 7-, 13-, and 24-month-old and their F344 x BN hybrid (F1) 7-, 13-, 24- and 31-month-old were tested in a behavioral battery (15-min and 24-h locomotor activity, inclined screen, rod suspension, rotorod, shock-motivated learning in a straight runway and 14-unit T maze). Necropsy was performed 3 days later and the results rated for pathology (i.e.

Time- and dose-dependent effects of the serotonergic agent quipazine on regional cerebral metabolism in rats.

The time course and the relation to dose of regional cerebral metabolic rates for glucose (rCMRglc) were measured in awake male adult Fischer-344 rats after administration of quipazine, a serotonin 5-HT2-3 receptor agonist. rCMRglc was determined, using the quantitative autoradiographic [14C]deoxyglucose technique, in 92 brain regions at 30, 60, 90 and 120 min after quipazine 20 mg/kg i.p.

Activation of cerebral blood flow during a visuoperceptual task in patients with Alzheimer-type dementia.

Changes in regional cerebral blood flow (rCBF) associated with a face-matching task were examined using positron emission tomography (PET) and H2(15)O in 7 patients with mild-moderate dementia of the Alzheimer type (DAT) and in 8 healthy age-matched controls. rCBF was normalized to whole brain flow and pixel-by-pixel difference images were computed by contrasting flow during a control task to flow during face matching. Both patients and controls showed bilateral rCBF increases in occipitotemporal extrastriate cortex during face matching.

Effects of nerve growth factor on electrical membrane properties of cultured dorsal root ganglia neurons from normal and trisomy 21 human fetuses.

Trisomy 21 (Down syndrome) results in abnormalities of electrical membrane properties of cultured human fetal dorsal root ganglion (DRG) neurons; namely, faster rates of depolarization and repolarization of the action potential, and a shortened spike duration. A possible role of nerve growth factor (NGF) in the expression of abnormal electrical membrane properties fetal human DRG neurons from trisomy 21 subjects was examined. DRG neurons obtained from normal and trisomy 21 abortuses of 16-20 weeks gestation were cultured in the presence or absence of 40 nM 7S NGF.

Replating improves whole cell voltage clamp recording of human fetal dorsal root ganglion neurons.

The whole cell patch clamp technique allows recording of membrane currents in an entire cell under voltage clamp conditions. However, technical difficulties arise in large cells bearing extensive processes, such as human fetal dorsal root ganglion (DRG) neurons in culture. In order to improve space clamp conditions, human fetal DRG neurons cultured for 1-2 weeks were enzymatically detached and replaced in new dishes, yielding round or oval cells with absent or short processes at 24 h in culture.